ABSTRACT This R21 exploratory grant is a resubmission application in response to the funding opportunity announcement number PAR-16-195, ?Research to Advance the Understanding and Management of the Multiple Organ Dysfunction Syndrome in Children?. Septic shock is a prevalent condition in the pediatric intensive care unit and one of the most common causes of multiple organ dysfunction syndrome (MODS). It follows that a better understanding of pediatric-specific septic shock biology will lead to a better understanding of pediatric MODS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role in clearance of low-density lipoprotein (LDL). Since LDL metabolism is closely linked to clearance of bacterial lipid moieties, recent studies have explored the role of PCSK9 in sepsis. In adults with sepsis, a PCSK9 loss of function mutation is associated with improved survival. This clinical observation was corroborated in experimental sepsis, wherein genetic ablation or pharmacologic inhibition of PCSK9 confers protection in adult mice challenged with polymicrobial sepsis. This raises the intriguing possibility of leveraging PCSK9 inhibition as a novel therapeutic strategy for sepsis. The availability of an FDA approved PCSK9 inhibitor further raises interest in this approach. We genotyped over 400 children with septic shock and found the opposite result. Among children with septic shock, a PCSK9 loss of function mutation is independently associated with increased risk of poor outcome, even after adjusting for illness severity and age. New to this resubmission, we now report that juvenile PCSK9 null mice have a higher mortality rate after polymicrobial sepsis, compared to wild type mice. We also now show that the inflammatory response of the immature liver is dramatically different than that of the adult liver. These results support our long-standing contention that novel sepsis therapies developed based on studies in adults and adult experimental models, might not be biologically appropriate for children, reflecting the strong influence of development on the host response to sepsis. These results also provide an opportunity to conduct mechanistic studies that are unique to the pediatric host and directly consider the influence of development on the host response to sepsis, and hence, the biology of pediatric MODS. This is the focus of our proposal. Using a juvenile model, in which we induce polymicrobial sepsis in 14-day-old mouse pups, we propose two Specific Aims. In Specific Aim 1, we will test the hypothesis that inhibition of PCSK9 is deleterious in a juvenile model of polymicrobial sepsis. This Aim will make use of PCSK9 null mice and a neutralizing anti-PCSK9 antibody. In Specific Aim 2, we will test the hypothesis that PCSK9 augments hepatic inflammation in a juvenile model of polymicrobial sepsis. This Aim will make use of LDL receptor null mice and gadolinium chloride-mediated Kupffer cell depletion. Collectively, the studies propose here will clarify the role of PCSK9 in pediatric sepsis and elucidate a novel mechanism of sepsis biology specific to the pediatric host.